Compositions comprising 2-hydroxycarboxylic acids and related compounds, and methods for alleviating signs of dermatological aging

ABSTRACT

Uses of topical compositions comprising a 2-hydroxycarboxylic acid or related compound to alleviate or improve signs of skin, nail and hair changes associated with intrinsic or extrinsic aging are disclosed. 2-Hydroxycarboxylic acids and their related compounds include, for example, 2-hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-methyl 2-hydroxypropanoic acid, 2-phenyl 2-hydroxyethanoic acid, 2-phenyl 2-methyl 2-hydroxyethanoic acid, 2-phenyl 3-hydroxypropanoic acid, 2,2-diphenyl 2-hydroxyethanoic acid, 2-hydroxybutane-1,4-dioic acid, 2,3-hihydroxybutane-1,4-dioic acid, 2-carboxy 2-hydroxypentane-1,5-dioic acid, 2-ketopropanoic acid, methyl 2-ketopropanoate, ethyl 2-ketopropanoate, and gluconolactone. Topical application of compositions comprising 2-hydroxycarboxylic acid and/or related compounds has been found to alleviate or improve skin lines; blotches; blemishes; nodules; wrinkles; pigmented spots; atrophy; precancerous lesions; elastotic changes characterized by leathery, coarse, rough, dry and yellowish skin; and other skin changes associated with intrinsic aging or skin damages caused by extrinsic factors such as sunlight, radiations, air pollution, wind, cold, dampness, heat, chemicals, smoke and cigarette smoking. Topical applications of such compositions have also been found to improve the overall qualities of nail and hair affected by intrinsic aging or damaged by extrinsic factors.

This application is a continuation of application Ser. No. 08/359,939,filed on Dec. 20, 1994, which is a continuation of Ser. No. 08/117,559,filed Sep. 7, 1993, now abandoned which is a continuation of Ser. No.07/936,863, filed Aug. 27, 1992, now abandoned which is a continuationof Ser. No. 07/683,437, filed Apr. 10. 1991, now abandoned which is acontinuation-in-part of Ser. No. 07/469,738, filed Jan. 19, 1990, nowabandoned which is a continuation of Ser. No. 06/945,680, filed Dec. 23,1986, now abandoned. This application is also a continuation-in-part ofSer. No. 07/393,749, filed Aug. 15, 1989, now U.S. Pat. No. 5,091,171.

FIELD OF THE INVENTION

This application relates to topical compositions containing a2-hydroxycarboxylic acid or a related compound for use in alleviating orimproving the dermatological signs of aging, including changes or damageto skin, nail and hair associated with intrinsic aging, as well aschanges or damage caused by extrinsic factors such as sunlight,radiations, air pollution, wind, cold, heat, dampness, chemicals, smoke,and cigarette smoking.

BRIEF DESCRIPTION OF THE PRIOR ART

In our U.S. Pat. No. 3,879,537 entitled "Treatment of IchthyosiformDermatoses" we described and claimed the use of topical compositionscontaining an alpha hydroxyacid to alleviate the symptoms of ichthyosis.In our U.S. Pat. No. 3,920,835 entitled "Treatment of DisturbedKeratinization" we described and claimed the use of topical compositionscontaining an alpha hydroxyacid to alleviate the symptoms of acne. Inour U.S. Pat. No. 3,984,566 entitled "Method of Alleviating the Symptomsof Dandruff" we described and claimed the use of topical compositionscontaining an alpha hydroxyacid to improve the symptoms of dandruff.

In our U.S. Pat. No. 4,105,783 entitled "Therapeutic Treatment of DrySkin"; U.S. Pat. No. 4,197,316 entitled "Treatment of Dry Skin"; andU.S. Pat. No. 4,380,549 entitled "Topical Treatment of Dry Skin"; wedescribed and claimed the use of topical compositions containing analpha hydroxyacid to alleviate or improve the symptoms of dry skin. Inour U.S. Pat. No. 4,234,599 entitled "Treatment of Skin Keratoses withAlpha Hydroxyacids and Related Compounds", we described and claimed theuse of topical compositions containing an alpha hydroxyacid or therelated compound to alleviate the symptoms of actinic or nonactinic skinkeratoses. In our U.S. Pat. No. 4,363,815 entitled "Alpha Hydroxyacids,Alpha Ketoacids and Their Use in Treating Skin Conditions", we describedand claimed the use of topical compositions containing certain alphahydroxyacids or the related compounds to improve skin conditionscharacterized by inflammation or disturbed keratinization.

In a report entitled "Topical Tretinoin for Photoaged Skin" by Albert M.Kligman, Gary L. Grove, Ryoji Hirose and James J. Leyden published in J.American Academy of Dermatology Vol.15, pages 836-859, 886-887, 1986,daily topical application of 0.05% tretinoin (also known as all-transretinoic acid) in a cream has been found to improve photodamaged skin.In another report entitled "Topical Tretinoin Improves Photoaged Skin: ADouble-blind Vehicle-controlled Study" by Jonathan S. Weiss, Charles N.Ellis, John T. Headington, Theresa Tincoff, Ted A. Hamilton and John J.Voorhees published in J American Medical Association Vol. 259 pages527-532, 1988, daily topical application of 0.1% tretinoin as comparedto vehicle alone application for 16 weeks has been shown to improvephotoaged skin. One side-effect has been a dermatitis encountered by 92%of the patients participating in this study. The dermatitis wascharacterized by a patchy erythema, localized swelling, dry skin, andmild scaling. Patients complained about burning, tingling, or pruritus.In yet another report entitled "Topical Tretinoin in the Treatment ofAging Skin" by Jonathan S. Weiss, Charles N. Ellis, John T. Headingtonand John J. Voorhees published in J. American Academy of DermatologyVol.19, pages 169-175, 1988, topical application of 0.1% tretinoin creamfor 8 to 12 months has been found to improve clinical signs of agingskin. The side effects have been burning sensation in the eyes and mildskin irritations.

Parent application Ser. No. 07/469,738 described in addition to the mainsubject certain compositions containing hydroxycarboxylic acids and therelated ketocarboxylic acids for topical treatment of wrinkles and skinchanges associated with aging. The related application of Ser. No.07/393,749 described in addition to the main subject a topical treatmentto alleviate or remedy warts, nail infections, age spots, wrinkles andaging related skin changes with a composition containing certain alphahydroxyacids or the related compounds. We have now discovered that2-hydroxycarboxylic acids and related compounds have much broaderutilization than previously disclosed.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide methods andcompositions which can alleviate signs of skin, nail and hair changesassociated with intrinsic and/or extrinsic aging.

We have now discovered that 2-hydroxycarboxylic acids and relatedcompounds have unusual qualities as well as broader utilities which havenot been disclosed in the prior art. Topical applications ofcompositions containing a 2-hydroxycarboxylic acid or a related compoundhave been found to improve cosmetic as well as clinical signs of changesin skin, nails and hair associated with intrinsic aging, or the damagescaused by extrinsic factors such as sunlight, radiations, air pollution,wind, cold, dampness, heat, chemicals, smoke, and cigarette smoking. Thesigns of skin changes associated with intrinsic aging and the skindamages caused by extrinsic factors include thinning of skin; deepeningof skin lines; wrinkles; blemishes; blotches; nodules; atrophy;pigmented spots; precancerous lesions; elastotic changes characterizedby leathery, coarse, rough, dry and yellowish skin; and telangiectaticskin. The signs of nails and hair changes associated with intrinsicaging and the damages caused by extrinsic factors include thinning,fragility, splitting, lack of luster, uneven surface, and loss offlexibility and elasticity. 2-Hydroxycarboxylic acids and their relatedcompounds which are useful for topical treatment of skin, nail and hairchanges associated with intrinsic and/or extrinsic aging include, interalia, 2-hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-methyl2-hydroxypropanoic acid, 2-phenyl 2-hydroxyehtanoic acid, 2-phenyl2-methyl 2-hydroxyethanoic acid, 2-phenyl 3-hydroxypropanoic acid,2,2-diphenyl 2-hydroxyethanoic acid, 2-hydroxybutane-1,4-dioicacid,2,3-dihydroxybutane-1,4-dioic acid, 2-carboxy 2-hydroxypentane-1,5-dioicacid, 2-ketopropanoic acid, methyl 2-ketopropanoate, ethyl2-ketopropanoate, and gluconolactone.

Additional objects and advantages of the invention will be set forth inpart in the description that follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and the advantages of this invention may be realized andobtained by means of the compositions and methods particularly pointedout in the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Cutaneous aging is associated with intrinsic factors with or without theadditional factors of extrinsic origin. The intrinsic aging is due tointernal physiologic functions and is an inherent aging process ofliving beings, which has not been reversible nor preventable. However, amodification, improvement or alleviation of the signs associated withcutaneous aging is now possible in accordance with this invention.Extrinsic aging, on the other hand, is due to external factors such assunlight, radiations, air pollution, wind, cold, dampness, heat,chemicals, smoke, and cigarette smoking. A modification, improvement oralleviation of the signs associated with the extrinsic aging of skin,nails and hair is also now possible in accordance with this invention.Moreover, in some cases, it may be possible to eradicate such signs ofintrinsic and extrinsic aging.

In the protected areas of skin such as abdomen and upper arm, the signsof skin aging which are caused by intrinsic factors include progressivethinning of skin, deepening of skin lines, wrinkles, dry and lusterlessskin surface, loss of skin elasticity and recoilability. In the sunexposed areas of skin such as face and hands, the signs of intrinsicaging plus those of photoaging include deep wrinkles; marked loss ofelasticity and recoilability; coarse, uneven and dry skin; blemished andleathery skin; loss of skin lubricating substances; and increasednumbers of blotches, nodules and pigmented spots.

Histologically, the qualities and quantities of elastin and collagentissues are changed. Normal elastin in tissues is replaced by abnormalelastin characterized as solar elastosis, and the normal collagen fibersare decreased.

The signs of nail and hair changes associated with intrinsic aging andthe damages caused by extrinsic factors include thinning of hair andnail plate; lack of lubricants and luster, and uneven surface of hairand nails; fragility and splitting of hair and nails; and reduction offlexibility, resiliency, and elasticity of hair and nails.

The conventional management for signs of aging skin has been the use ofcosmetics as well as medical procedures such as phenol, trichloroaceticacid, and other chemical peels, and plastic surgery etc. Such medicalprocedures are costly and risky with serious side effects, and thetreatments alter only the cosmetic appearance of the skin, without anysignificant modifications of the underlying aging process.

As mentioned in the previous section, recent medical reports claimed theuse of topical compositions containing tretinoin to improve clinicalsigns of skin aging associated with intrinsic factors as well as theskin damages caused by sunlight. However, use of tretinoin has beenassociated with certain adverse skin reactions such as dry skin,scaling, burning, tingling, itching, erythema, skin dermatitis,localized swelling, and induction of photosensitivity.

We have now discovered that use of topical compositions containing2-hydroxycarboxylic acid or related compounds are therapeuticallyeffective in modification or eradication of clinical signs of cutaneousaging with minimal if any side effects or discomfort.

For convenience, the 2-hydroxycarboxylic acids and related compoundswhich may be used in accordance with this invention may be classifiedinto three groups, namely (1) 2-hydroxycarboxylic acids, (2)2-ketocarboxylic acids and esters thereof, and (3) other relatedcompounds. The related compounds may include hydroxycarboxylic acidswith the hydroxyl group at any position other than position 2, forexample position 3, position 4 or position 5, as well as cyclichydroxycarboxylic acids (e.g., ascorbic acid and quinic acid), and alsomay include ketocarboxylic acids and esters thereof. Preferred relatedcompounds include 3-hydroxycarboxylic acids, and 2-ketocarboxylic acidsand esters thereof.

Group 1

The first group comprises organic carboxylic acids in which one hydroxygroup is attached to the 2 position carbon atom of the acid. The genericstructure of such 2-hydroxycarboxylic acids may be represented asfollows:

    (R.sub.a)(R.sub.b)C(OH)COOH

Where R_(a) and R_(b) may be the same or different and are independentlyselected from H, F, Cl, Br, alkyl, aralkyl or aryl group of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 29 carbon atoms, and in addition R_(a) andR_(b) may carry OH, CHO, COOH and alkoxy group having 1 to 9 carbonatoms. 2-Hydroxycarboxylic acids may be present as a free acid orlactone form, or in a salt form with an organic base or an inorganicalkali. 2-Hydroxycarboxylic acids may exist as stereoisomers as D, L,and DL forms when R_(a) and R_(b) are not identical.

Typical alkyl, aralkyl and aryl groups for R_(a) and R_(b) includemethyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, decyl, dodecyl,hexadecyl, benzyl, and phenyl, etc. 2-Hydroxycarboxylic acids of thefirst group may be further divided into subgroups comprising (1) alkylhydroxycarboxylic acids, (2) aralkyl and aryl hydroxycarboxylic acids,(3) polyhydroxy-carboxylic acids, and (4) hydroxy-polycarboxylic acids.The following are representative 2-hydroxycarboxylic acids in eachsubgroup.

(1) Alkyl Hydroxycarboxylic Acids

1. 2-Hydroxyethanoic acid (Glycolic acid, hydroxyacetic acid)

(H) (H) C (OH) COOH

2. 2-Hydroxypropanoic acid (Lactic acid)

(CH₃) (H) C (OH) COOH

3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)

(CH₃) (CH₃) C (OH) COOH

4. 2-Hydroxybutanoic acid

(C₂ H₅) (H) C (OH) COOH

5. 2-Hydroxypentanoic acid

(C₃ H₇) (H) C (OH) COOH

6. 2-Hydroxyhexanoic acid

(C₄ H₉) (H) C (OH) COOH

7. 2-Hydroxyheptanoic acid

(C₅ H₁₁) (H) C (OH) COOH

8. 2-Hydroxyoctanoic acid

(C₆ H₁₃) (H) C (OH) COOH

9. 2-Hydroxynonanoic acid

(C₇ H₁₅) (H) C (OH) COOH

10. 2-Hydroxydecanoic acid

(C₈ H₁₇) (H) C (OH) COOH

11. 2-Hydroxyundecanoic acid

(C₉ H₁₉) (H) C (OH) COOH

12. 2-Hydroxydodecanoic acid (Alpha hydroxylauric acid)

(C₁₀ H₂₁) (H) C (OH) COOH

13. 2-Hydroxytetradecanoic acid (Alpha hydroxymyristic acid)

(C₁₂ H₂₅) (H) C (OH) COOH

14. 2-Hydroxyhexadecanoic acid (Alpha hydroxypalmitic acid)

(C₁₄ H₂₉) (H) C (OH) COOH

15. 2-Hydroxyoctadecanoic acid (Alpha hydroxystearic acid)

(C₁₆ H₃₃) (H) C (OH) COOH

16. 2-Hydroxyeicosanoic acid (Alpha hydroxyarachidonic acid)

(C₁₈ H₃₇) (H) C (OH) COOH

17. 2-Hydroxytetraeicosanoic acid (Cerebronic acid)

(C₂₂ H₄₅) (H) C (OH) COOH

18. 2-Hydroxytetraeicosenoic acid (Alpha hydroxynervonic acid)

(C₂₂ H₄₃) (H) C (OH) COOH

(2) Aralkyl And Aryl 2-Hydroxycarboxylic Acids

1. 2-Phenyl 2-hydroxyethanoic acid (Mandelic acid)

(C₆ H₅) (H) C (OH) COOH

2. 2,2-Diphenyl 2-hydroxyethanoic acid (Benzilic acid)

(C₆ H₅) (C₆ H₅) C (OH) COOH

3. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)

(C₆ H₅ CH₂) (H) C (OH) COOH

4. 2-Phenyl 2-methyl 2-hydroxyethanoic acid (Atrolactic acid)

(C₆ H₅) (CH₃) C (OH) COOH

5. 2-(4'-Hydroxyphenyl) 2-hydroxyethanoic acid

(4-Hydroxymandelic acid)

(HO--C₆ H₄) (H) C (OH) COOH

6. 2-(4'-Chlorophenyl) 2-hydroxyethanoic acid

(4-Chloromandelic acid)

(Cl--C₆ H₄) (H) C (OH) COOH

7. 2- (3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid

(3-Hydroxy-4-methoxymandelic acid)

(HO--, CH₃ O--C₆ H₃) (H) C (OH) COOH

8. 2-(4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid

(4-Hydroxy-3-methoxymandelic acid)

(HO--, CH₃ O--C₆ H₃) (H) C (OH) COOH

9. 3-(2'-Hydroxyphenyl) 2-hydroxypropanoic acid

[3-(2'Hydroxyphenyl) lactic acid]

(HO--C₆ H₄ --CH₂) (H) C (OH) COOH

10. 3-(4'-Hydroxyphenyl ) 2 -hydroxypropanoic acid

[3-(4'-Hydroxyphenyl) lactic acid]

(HO--C₆ H₄ --CH₂) (H) C (OH) COOH

11. 2-(3', 4'-Dihydroxyphenyl ) 2 -hydroxyethanoic acid

(3,4-Dihydroxymandelic acid)

(HO--, HO--C₆ H₃) (H) C (OH) COOH

(3) Polyhydroxy-carboxylic Acids

1. 2,3-Dihydroxypropanoic acid (Glyceric acid)

(HOCH₂) (H) C (OH) COOH

2. 2,3,4-Trihydroxybutanoic acid (Isomers; erythronic acid, threonicacid)

(HOCH₂ HOCH) (H) C (OH) COOH

3. 2,3,4,5-Tetrahydroxypentanoic acid (Isomers; ribonic acid, arabinoicacid, xylonic acid, lyxonic acid)

(HOCH₂ HOCH HOCH) (H) C (OH) COOH

4. 2,3,4,5,6-Pentahydroxyhexanoic acid (Isomers; allonic acid, altronicacid, gluconic acid, mannoic acid, gulonic acid, idonic acid, galactonicacid, talonic acid)

(HOCH₂ HOCH HOCH HOCH) (H) C (OH) COOH

5. 2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers; glucoheptonic acid,galactoheptonic acid etc.)

(HOCH₂ HOCH HOCH HOCH HOCH) (H) C (OH) COOH

(4) Hydroxy-polycarboxylic Acids

1. 2-Hydroxypropane-1,3-dioic acid (Tartronic acid)

(HOOC) (H) C (OH) COOH

2. 2-Hydroxybutane-1,4-dioic acid (Malic acid)

(HOOC CH₂) (H) C (OH) COOH

3. 2,3-Dihydroxybutane-1,4-dioic acid (Tartaric acid)

(HOOC HOCH) (H) C (OH) COOH

4. 2-Hydroxy-2-carboxypentane-1,5-dioic acid (Citric acid)

(HOOC CH₂)₂ C (OH) COOH

5. 2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers; saccharic acid,mucic acid etc.)

HOOC (CHOH)₄ COOH

The 2-hydroxycarboxylic acids may be present in forms other than theacid, such as, for example, salts or lactones. Typical lactone formswhich may be used in accordance with this invention include, forexample, gluconolactone, galactonolactone, glucuronolactone,galacturonolactone, gulonolactone, ribonolactone, saccharic acidlactone, pantoyllactone, glucoheptonolactone, mannonolactone, andgalactoheptonolactone.

The second group, which comprises compounds related to the2-hydroxycarboxylic acids, includes organic carboxylic acids in whichone keto group is attached to position 2 carbon atom of the acid. Thegeneric structure of such 2-ketoacids may be represented as follows:

    (R.sub.c) CO COO (R.sub.d)

wherein R_(c) and R_(d) can be the same or different and are eachselected from H, alkyl, aralkyl or aryl group of saturated orunsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 29 carbon atoms, and in addition R_(c) maycarry F, Cl, Br, I, OH, CHO, COOH and alkoxy group having 1 to 9 carbonatoms. The alpha ketoacids may be present as a free acid or an esterform, or in a salt form with an organic base or an inorganic alkali. Thetypical alkyl, aralkyl and aryl groups for R_(c) and R_(d) includemethyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, octyl, dodecyl,hexadecyl, benzyl and phenyl.

In contrast to 2-hydroxycarboxylic acids of the first group compounds,the ester form of 2-ketocarboxylic acids has been found to betherapeutically effective for signs and symptoms of cutaneous agingincluding intrinsic and extrinsic aging. For example, while methyl2-hydroxypropanoate and ethyl 2-hydroxypropanoate have minimal effects,methyl 2-ketopropanoate and ethyl 2-ketopropanoate are therapeuticallyvery effective. The real mechanism for such difference is not known. Wehave speculated that the ester form of the 2-ketocarboxylic acid ischemically and/or biochemically very reactive, and a free2-ketocarboxylic acid may be released in the skin after penetrationthrough the stratum corneum of the skin. The representative2-ketocarboxylic acids and their esters of the second group are listedbelow:

1. 2-Ketoethanoic acid (Glyoxylic acid)

(H) CO COOH

2. Methyl 2-ketoethanoate

(H) CO COOCH₃

3. 2-Ketopropanoic acid (Pyruvic acid)

CH₃ CO COOH

4. Methyl 2-ketopropanoate (Methyl pyruvate)

CH₃ CO COOCH₃

5. Ethyl 2-ketopropanoate (Ethyl pyruvate)

CH₃ CO COOC₂ H₅

6. Propyl 2-ketopropanoate (Propyl pyruvate)

CH₃ CO COOC₃ H₇

7. 2-Phenyl-2-ketoethanoic acid (Benzoylformic acid)

C₆ H₅ CO COOH

8. Methyl 2-phenyl-2-ketoethanoate (Methyl benzoylformate)

C₆ H₅ CO COOCH₃

9. Ethyl 2-phenyl-2-ketoethanoate (Ethyl benzoylformate)

C₆ H₅ CO COOC₂ H₅

10. 3-Phenyl-2-ketopropanoic acid (Phenylpyruvic acid)

C₆ H₅ CH₂ CO COOH

11. Methyl 3-phenyl-2-ketopropanoate (Methyl phenylpyruvate)

C₆ H₅ CH₂ CO COOCH₃

12. Ethyl 3-phenyl-2-ketopropanoate (Ethyl phenylpyruvate)

C₆ H₅ CH₂ CO COOC₂ H₅

13. 2-ketobutanoic acid

C₂ H₅ CO COOH

14. 2-Ketopentanoic acid

C₃ H₇ CO COOH

15. 2-Ketohexanoic acid

C₄ H₉ CO COOH

16. 2-Ketoheptanoic acid

C₅ H₁₁ CO COOH

17. 2-Ketooctanoic acid

C₆ H₁₃ CO COOH

18. 2-Ketododecanoic acid

C₁₀ H₂₁ CO COOCH

19. Methyl 2-ketooctanoate

C₆ H₁₄ CO COOCH₃

Group 3

The third group, which also comprises related compounds, includes, interalia, hydroxycarboxylic acids where the hydroxy is at a position otherthan position 2, and cyclic hydroxycarboxylic acids which are useful fortopical application to improve signs of aging skin and the cutaneousappendages. The members of this group, which are more convenientlyidentified by name than by generic structures, include ascorbic acid,quinic acid, isocitric acid, tropic acid (2-phenyl 3-hydroxypropanoicacid), trethocanic acid, 3-chlorolactic acid, citramalic acid, agaricicacid, aleuritic acid, pantoic acid, lactobionic acid and hexulosonicacid.

Amplifying Bioactivities of Cosmetic and Pharmaceutical Agents

The compositions of present invention may contain one or more2-hydroxycarboxylic acids or related compounds to magnify thetherapeutic effect of an unrelated cosmetic or pharmaceutical agent. Atleast one compound selected from the group consisted of2-hydroxycarboxylic acids and related compounds may be incorporated intoa composition containing a cosmetic or pharmaceutical agent for topicaltreatment to improve or alleviate signs of skin, nails or hair changesassociated with intrinsic aging or the damages caused by extrinsicfactors. It has been found that such incorporation have resulted inmagnified therapeutic efficacies which are not simply additive effects.

Most pharmaceutical drugs produce their therapeutic effects by firstinteracting with their receptors in the target tissues. Many drugreceptors are functional macromolecules such as enzymes, cell membranecomponents or certain components of cells. The binding affinity orinteracting property of a drug toward its specific receptor molecule isintimately governed by the chemical structure of the drug. Since mostpharmaceutical agents are chemically different from 2-hydroxycarboxylicacids and related compounds, the respective receptor molecules should bedifferent and so are the pharmacologic actions and the therapeuticeffects. Under such conditions if 2-hydroxycarboxylic acid or a relatedcompound is incorporated into a composition containing a pharmaceuticalagent, one of the following two consequences may arise:

(a) No enhancement or any substantial changes in either effect. In thiscase, the overall clinical effect would be a mixing effect, i.e. theeffect due to the pharmaceutical agent alone mixed with the effect dueto the 2-hydroxycarboxylic acid or the related compound alone. Also inthis case, the interaction between the pharmaceutical agent and itsreceptor molecule is not affected nor interfered by the presence of2-hydroxycarboxylic acid or the related compound. Nor does2-hydroxycarboxylic acid or the related compound assist in or enhancethe binding affinity or the interaction of the pharmaceutical agenttoward its receptor molecule. The clinical results from such combinationcomposition would be just the mixing effects, and are predictable.

(b) Amplified therapeutic action or substantial loss of therapeuticaction in either effect. In this case, the interaction between thepharmaceutical agent and its receptor molecule is affected eitherpositively or negatively by the presence of 2-hydroxycarboxylic acid orthe related compound. From the point of positive effect,2-hydroxycarboxylic acid or the related compound may produce anamplified effect by either increasing the affinity of the receptormolecule toward the pharmaceutical agent; acting as a better and moreefficient coenzyme or as an activator by disrupting barriers andremoving obstacles for better binding of the agent toward its receptormolecule; for example, enzyme activation by removal of naturalinhibitors. In all these cases the overall clinical results would be dueto magnified therapeutic effects which are not predictable from eithereffect alone.

From the point of negative effect, a 2-hydroxycarboxylic acid or arelated compound might interfere with or decrease the binding affinityof the pharmaceutical agent toward its receptor molecule; i.e. acting asan inhibitor. In such case, the overall clinical results should be dueto a substantial diminishment or completely loss of therapeutic effects,which is also unpredictable from either effect alone.

We have found that, in most cases, therapeutic effects of cosmetic andpharmaceutical agents are amplified when a 2-hydroxycarboxylic acid or arelated compound is incorporated into the composition, i.e., consequence(b) above is observed.

The cosmetic and pharmaceutical agents which may be actuated by2-hydroxycarboxylic acids or related compounds include those thatimprove or eradicate age spots, keratoses and wrinkles by differentmechanism of action; antimicrobial and antiacne agents; antipruritic andantixerotic agents; antiinflammatory agents; sunscreen andantiphotosensitive agents; nail and hair conditioners, cleansers, careand treatment agents; wart removers; skin lightening agents;depigmenting agents; local anesthetics and analgesics; corticosteroids;retinoids; vitamins; hormones; and antimetabolites.

Some examples of cosmetic and pharmaceutical agents include acyclovir,amphotericins, chlorhexidine, clotrimazole, ketoconazole, miconazole,metronidazole, minocycline, nystatin, neomycin, kanamycin, phenytoin,octyl dimethyl PABA, octyl methoxycinnamate, PABA and other esters,octyl salicylate, oxybenzone, dioxybenzone, tocopherol, tocopherylacetate, selenium sulfide, zinc pyrithione, soluble elastin,diphenhydramine, pramoxine, lidocaine, procaine, erythromycin,tetracycline, clindamycin, hydroquinone and its monomethyl and benzylethers, naproxen, ibuprofen, cromolyn, retinoic acid, retinol, retinylpalmitate, retinyl acetate, coal tar, griseofulvin, hydrocortisone,hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone17-butyrate, betamethasone valerate, betamethasone dipropionate,triamcinolone acetonide, fluocinonide, clobetasol propionate, minoxidil,dipyridamole, diphenylhydantoin, benzoyl peroxide and 5-fluorouracil.

Specific Compositions For Skin And Skin Appendages

While 2-hydroxycarboxylic acids and related compounds aretherapeutically effective for topical treatment to improve or alleviatesigns of skin, nail or hair changes associated with intrinsic agingand/or photoaging, certain compounds of the instant invention are morepotent than others. In selecting a particular compound of the presentinvention two factors, namely (a) potency and (b) concentration have tobe considered. If rapid results are preferred in certain cases, mostpotent compounds with highest and safe concentrations may be used. Undersuch conditions the treatment time is substantially shortened with goodto excellent clinical results. Generally, such treatment has to becarried out under supervision by a dermatologist or trained professionalin the office, medical center, skin care center, or beauty salon etc.Such procedure or treatment may include micro and semimicro peels,epidermolysis or superficial peel, and dermolysis or deeper peel.

Examples of more potent 2-hydroxycarboxylic acids and related compoundsto be formulated in specific compositions include 2-hydroxyethanoicacid, 2-hydroxypropanoic acid, 2-methyl 2-hydroxypropanoic acid,2-phenyl 2-hydroxyethanoic acid, 2,2-diphenyl 2-hydroxyethanoic acid,2-phenyl 2-methyl 2-hydroxyethanoic acid, 2-phenyl 3-hydroxypropanoicacid, 2-ketopropanoic acid, methyl 2-ketopropanoate and ethyl2-ketopropanoate. The concentration of 2-hydroxycarboxylic acid or therelated compound used in such specific composition may range from anintermediate to a full strength, therefore the dispensing and theapplication require special handling and procedures.

If the 2-hydroxycarboxylic acid or the related compound at full strength(usually 85-100%) is a liquid form at room temperature such as2-hydroxypropanoic acid, 2-ketopropanoic acid, methyl 2-ketopropanoateand ethyl 2-ketopropanoate, the liquid compound with or without agelling agent is directly dispensed as 0.5 to 1 ml aliquots in smallvials.

If the 2-hydroxycarboxylic acid or the related compound at full strengthis a crystalline or solid form at room temperature such as2-hydroxyethanoic acid, 2-methyl 2-hydroxypropanoic acid, 2-phenyl2-hydroxyethanoic acid, 2,2-diphenyl 2-hydroxyethanoic acid and 2-phenyl3-hydroxypropanoic acid, the crystalline or solid compound is firstdissolved in a minimal amount of vehicle or vehicle system prepared fromwater, ethanol, propylene glycol and/or butylene glycol with or withouta gelling agent. For example, 2-hydroxyethanoic acid 70 g is dissolvedin water 30 ml, and the 70% strength solution thus obtained is dispensedas 0.5 to 1 ml aliquots in small vials. If a gelling agent is used 0.1to 2% of hydroxyethyl cellulose, methyl cellulose, hydroxypropylcellulose, chitosan, carbomer, or polyquaternium-10 may be incorporatedinto the above solution.

To formulate an intermediate strength (usually 20-50%),2-hydroxycarboxylic acid or the related compound either a liquid orsolid form at room temperature is first dissolved in a vehicle orvehicle system prepared from water, acetone, ethanol, propylene glycoland/or butylene glycol. For example, 2-hydroxyethanoic acid or2-ketopropanoic acid 30 g is dissolved in ethanol 56 g and propyleneglycol 14 g, and the 30% strength solution thus obtained is dispensed as7 to 14 ml aliquots in dropper bottles.

General Preparation of Compositions

Most compositions of the instant invention may be formulated assolution, gel, lotion, cream, ointment, or other pharmaceuticallyacceptable form. To prepare a composition in solution form for generaluse, at least one 2-hydroxycarboxylic acid or related compound isdissolved in a solution prepared from ethanol, water, propylene glycol,butylene glycol, acetone or other pharmaceutically acceptable vehicle.The concentration of the 2-hydroxycarboxylic acid or related compoundmay range from 0.1 to 100 percent, the preferred concentration rangesbeing from about 2 to about 25 percent for home use, with higher ranges,e.g., from about 70 to about 100 percent being acceptable for office usewhere professional supervision is provided. Thus, such concentrationscan also range from about 25 to about 50 percent and from about 50 toabout 70 percent, with the proviso that concentrations of about 25percent or more generally requiring profession supervision.

In the preparation of a composition in lotion, cream or ointment form,at least one of 2-hydroxycarboxylic acids or related compounds isinitially dissolved in a solvent such as water, ethanol, butyleneglycol, and/or propylene glycol. The solution thus prepared is thenmixed in a conventional manner with commonly available cream or ointmentbase such as hydrophilic ointment or petrolatum. The concentrations of2-hydroxycarboxylic acids or related compounds used in the compositionsare the same as described above.

Thin gel compositions are specifically useful for topical application tohair and face. A typical gel composition of the instant invention isformulated by dissolving at least one of 2-hydroxycarboxylic acids orrelated compounds in a vehicle prepared from ethanol, water, butyleneglycol, and/or propylene glycol. A gelling agent such as xanthan gum,polyquaternium-10, methyl cellulose, ethyl cellulose,hydroxyethylcellulose, hydroxypropylcellulose, chitosan,hydroxypropylmethylcellulose, ammoniated glycyrrhizinate or carbomer isthen added to the solution with agitation. The preferred concentrationof the gelling agent may range from 0.1 to 2 percent by weight of thetotal composition.

To prepare an actuated composition, a cosmetic or pharmaceutical agentis incorporated into any one of the above formulations by dissolving ormixing the agent into the composition.

The following are illustrative examples of formulations and compositionsaccording to this invention. Although the examples utilize only selectedcompounds and formulations, it should be understood that the followingexamples are illustrative and not limited. Therefore, any of theaforementioned 2-hydroxycarboxylic acids and related compounds may besubstituted according to the teachings of this invention in thefollowing examples.

EXAMPLE 1

A typical solution composition containing 2-hydroxycarboxylic acid orthe related compound may be formulated as follows. 2-Hydroxyethanoicacid (glycolic acid) crystals 7 g is dissolved in water 50 ml andpropylene glycol 15 ml. Ethanol is added to the solution until the totalvolume is 100 ml. The composition thus prepared contains 7% w/v2-hydroxyethanoic acid.

EXAMPLE 2

A typical gel composition containing 2-hydroxycarboxylic acid or therelated compound may be formulated as follows.

2-Hydroxypropanoic acid (DL-lactic acid) USP grade 5 g is dissolved inwater 60 ml and butylene glycol 10 ml, and chitosan or polyquaternium-100.3 g is added with stirring. Ethanol is added to the mixture until thevolume is 100 ml. The mixture is stirred until a uniform gel isobtained. The thin gel thus obtained contains 5% 2-hydroxypropanoicacid.

EXAMPLE 3

A typical oil-in-water emulsion containing 2-hydroxycarboxylic acid orthe related compound may be formulated as follows.

2-Methyl 2-hydroxypropanoic acid (methyllactic acid) crystals 10 g isdissolved in water 20 ml and concentrated ammonium hydroxide 2 ml isadded to the solution. The solution is mixed with enough hydrophilicointment USP to make a total weight of 100 g. The cream thus formulatedcontains 10% 2-methyl 2-hydroxypropanoic acid.

EXAMPLE 4

A typical water-in-oil emulsion containing 2-hydroxycarboxylic acid orthe related compound may be formulated as follows.

Gluconolactone 7 g is dissolved in water 12 ml and concentrated ammoniumhydroxide 0.5 ml is added to the solution. The solution is mixed withenough water-in-oil emulsion to make a total weight of 100 g. The waternon-washable cream thus formulated contains 7% gluconolactone.

EXAMPLE 5

A typical ointment containing 2-hydroxycarboxylic acid or the relatedcompound may be formulated as follows.

2-Phenyl 2-hydroxyethanoic acid (mandelic acid) crystals 10 g isdissolved in 10 ml ethanol, and the solution thus formed is mixed withmineral oil 35 g and enough white petrolatum to make a total weight of100 g. The ointment thus formulated contains 10% 2-phenyl2-hydroxyethanoic acid.

EXAMPLE 6

A specific preparation containing a full strength or a highconcentration of 2-hydroxycarboxylic acid or the related compound may beformulated and dispensed as follows.

If 2-hydroxycarboxylic acid or the related compound at full strength isa liquid form at room temperature such as 2-hydroxypropanoic acid,2-ketopropanoic acid, methyl 2-ketopropanoate and ethyl2-ketopropanoate, the compound is directly dispensed as 0.5 to 1 mlaliquots in small vials. If the compound is a crystalline or solid form,such as 2-hydroxyethanoic acid, 2-methyl 2-hydroxypropanoic acid,2-phenyl 2-hydroxyethanoic acid, 2-phenyl 3-hydroxypropanoic acid,2-phenyl 2-methyl 2-hydroxyethanoic acid and 2,2-diphenyl2-hydroxyethanoic acid, the compound is first dissolved in minimalamount of an appropriate vehicle system selected from water, ethanol,propylene glycol and butylene glycol with or without a gelling agent.For example, 2-hydroxyethanoic acid 70 g is dissolved in water 30 ml,and 70% strength 2-hydroxyethanoic acid with or without addition of 0.5%chitosan or polyquaternium-10 is dispensed as 1 to 5 ml aliquots insmall vials.

EXAMPLE 7

A typical preparation containing an intermediate strength of2-hydroxycarboxylic acid or the related compound may be formulated asfollows.

Malic acid, tartaric acid or citric acid 35 g is dissolved in water 60ml and propylene glycol 5 ml. The 35% strength solution thus prepared isdispensed as 5 to 10 ml aliquots in dropper bottles.

EXAMPLE 8

A composition containing 2-hydroxycarboxylic acid or the relatedcompound to magnify the therapeutic effect of a cosmetic orpharmaceutical agent for wrinkles and other signs of skin aging may beformulated as follows.

Ethyl 2-ketopropanoate (ethyl pyruvate) 2 g and all-trans retinoic acid0.02 g are dissolved in a vehicle system prepared from ethanol 50 ml,water 28 ml and propylene glycol 20 ml. The composition thus formulatedcontains retinoic acid 0.02% and ethyl 2-ketopropanoate 2%.

EXAMPLE 9

A composition containing 2-hydroxycarboxylic acid or the relatedcompound to amplify the therapeutic effect of a dermatologic agent forblemishes, pigmented spots and wrinkles may be formulated as follows.

2-Hydroxyethanoic acid 8 g, hydroquinone 2 g and sodium metabisulfite0.4 g are dissolved in a vehicle prepared from ethanol 30 ml, water 45ml and propylene glycol 15 ml. Chitosan or polyquaternium-10 0.3 g isadded to the solution with stirring. The mixture is stirred until auniform gel is obtained. The thin gel thus obtained containshydroquinone 2% and 2-hydroxyethanoic acid 8%.

EXAMPLE 10

A typical cleansing and soothing composition containing2-hydroxycarboxylic acid or the related compound to enhance thetherapeutic effect of a dermatologic agent for initial treatment of hairor skin changes associated with aging may be formulated as follows.

2,2-Diphenyl 2-hydroxyethanoic acid (benzilic acid) 2 g andchlorhexidine 0.3 g are dissolved in a vehicle system prepared fromethanol 30 ml, water 58 ml and butylene glycol 10 ml. The solution thusformulated contains chlorhexidine 0.3% and 2,2-diphenyl2-hydroxyethanoic acid 2%.

EXAMPLE 11

A typical lotion containing 2-hydroxycarboxylic acid or the relatedcompound to substantiate and magnify the sunscreen effect of adermatologic agent may be formulated as follows.

2-Hydroxyethanoic acid 3 g and concentrated ammonium hydroxide 0.75 mlare dissolved in water 7 ml, and the solution thus obtained is mixedwith 85 g of an oil-in-water emulsion which contains octylmethoxycinnamate 5 g. The actuated sunscreen lotion thus formulatedcontains 5% sunscreen agent and 3% 2-hydroxyethanoic acid.

TEST RESULTS

(1) Biologic and Pharmacologic Actions

The skin may be classified into two major parts; dermis and epidermis.The dermis contains blood vessels, nerves, collagen, elastin etc, andfibroblast cells in the dermis are responsible for the biosynthesis ofcollagen and elastin. The epidermis contains nerves but no collagen,elastin, nor blood vessels.

The epidermis is further divided into two distinct zones; malpighianlayer and horny layer. The malpighian layer, a living tissue, is furtherdivided into basal, spinous, and granular layers. The horny layer, adead tissue, is also called stratum corneum. In the natural process,basal cells in the basal layer move outward through the spinous andgranular layers to become dead cells called corneocytes, in the stratumcorneum. The stratum corneum consists of approximately 14 layers ofcorneocytes. In normal skin it takes about 14 days for the basal cellsto move from the basal layer to the end of the granular layer and tobecome corneocytes, and another 14 days to reach the outermost layer ofthe stratum corneum. This process of forming corneocytes is calledkeratinization, and stratum corneum, nail, and hair are the naturalproducts produced by such process. The stratum corneum is the skintissue that one feels when touching the skin. Usually, it takes about 28days for cells of the basal layer to move outward to the surface in thecourse of making new skin.

We have found that compositions containing low concentrations of2-hydroxycarboxylic acid or the related compound, when applied topicallyto the skin, diminish corneocyte cohesion in the stratum corneum. Thiseffect predominantly occurs among corneocyte cells at inner levels ofthe stratum corneum, i.e. near the junction to the granular layer, andthere is no effect among corneocyte cells at outer layers in the stratumcorneum. Therefore, 2-hydroxycarboxylic acids and related compounds arenot typical keratolytics such as strong acids, strong alkalis, thiols,urea and lithium salts which cause disaggregation of corneocyte cells inthe-"outer layers of the stratum corneum.

We have also discovered that compositions containing intermediate tohigh concentrations of 2-hydroxycarboxylic acid or the related compound,when topically applied to the skin, cause profound beneficial effects inthe dermis as well as the epidermis of the skin. The skin becomesthicker and plump as measured clinically by caliper and micrometertechniques. Histometric techniques using microscopic analysis of tissuebiopsy specimens confirm that new and more collagen and elastic fibershave been biosynthesized in the dermis.

The biologic and pharmacologic actions of 2-hydroxycarboxylic acid orthe related compound suggest that topical application of the compositionshould improve or alleviate signs of skin, nail, and hair changesassociated with intrinsic and/or extrinsic aging.

(2) Therapeutic Effects

In order to determine whether compositions containing2-hydroxycarboxylic acid or the related compound were therapeuticallyeffective for topical application to improve or alleviate signs of skin,nail, and hair changes associated with intrinsic and/or extrinsic aging,a total of more than 120 volunteers and patients participated in thesestudies. Intrinsic aging is due to internal physiologic process,different from the damage caused by an external factor such as sunlight.The body areas showing predominantly intrinsic aging are in theprotected regions of the skin such as abdomen, buttock, and upper arm.The signs of intrinsic aging include thinning of skin, deepening ofnatural skin lines, fine wrinkles, dry and lusterless skin surface, lossof skin elasticity and recoilability. Therefore, for intrinsic agingtest compositions were topically applied to the skin of upper armsand/or abdomen.

The extrinsic aging is a progressive damage caused by environmentalfactors such as sunlight, radiations, air pollution, wind, cold,dampness, heat, chemicals, smoke, and/or smoking. The body areaspredominantly involved are in the exposed regions of the skin such asface, scalp with thin or no hair, neck, forearms, and the back of hands.The signs of extrinsic aging in these skin areas are in most cases acombination of intrinsic aging and extrinsic aging unless it involves avery young person. The signs of both intrinsic and extrinsic aginginclude fine and deep wrinkles, loss of elasticity and recoilability,coarse and very dry skin, blemished and leathery skin, loss of skinlubricants, and increased numbers of age spots, blotches, nodules andpigmented spots. In such cases test compositions were topically appliedto face, forearms, and the back of hands.

The composition containing a weak to intermediate concentration of2-hydroxycarboxylic acid or the related compound was topically appliedto the skin by a patient or a participating subject at home, as a hometreatment. The composition containing a high concentration or a fullstrength of 2-hydroxycarboxylic acid or the related compound wastopically applied to the involved skin of a patient, such as the face,by a dermatologist or a trained health professional as an officeprocedure or treatment. For rapid therapeutic results, both home andoffice treatments were adopted in many cases.

(a) Home Treatment

In order to determine whether the composition containing a2-hydroxycarboxylic acid or related compound was therapeuticallyeffective for topical application to alleviate or improve signs of skinchanges associated with intrinsic and extrinsic aging on the face or theback of hands, both patients and volunteer subjects were included in thestudy. The compositions containing 5 to 30%, and preferably between 8 to20%, of a 2-hydroxycarboxylic acid or related compound were formulatedwith optimal bioavailability of the active ingredient according to theexamples. The participants were instructed to apply the compositionstwice daily on the face and the back of hands for intervals of 2 to 12months. All participants were instructed to avoid sun exposure, and touse-a sunscreen product with a sun protection factor of 15 or greater ifexposure to sunlight was unavoidable.

Photographs of each side of the face, and the back of hands were takenat the beginning of the study and repeated at one to three-monthintervals. The participants were asked not to wear facial makeup nor toapply any products on the back of hands at the time of the visit, exceptfor eye shadow if desired. Standardized photographic conditions wereused: the same light source at two feet from the face aimed at a locuson the frontal aspect of each cheek, and also at two feet from the backof hands. Photographs were taken with the camera aimed perpendicular tothe cheek or the back of hands.

After 2 months of home treatment all of a group of 35 participantsshowed substantial improvement of the face and the back of hands. Theskin was smoother, glossy, and softer. Blotches, blemishes, and agespots on the face were also decreased in number or were lighter in colorin a group of 30 out of 35 closely monitored participants. After 6 to 9months of continued home treatment, skin lines and fine wrinkles on theface either disappeared or were diminished in 24 out of this group ofparticipants. Great numbers of age spots and blemishes on the face andthe back of hands also continued to disappear or become much lessconspicuous. The skin appeared and felt smooth, soft, and glossy.Coarser wrinkles were substantially reduced after months of continuedhome treatment.

(b) Office Treatment

Specific compositions containing a high concentration to a full strengthof a 2-hydroxycarboxylic acid or related compound were used in mostcases as an office procedure or treatment. The composition containing2-hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-ketopropanoic acid,2-methyl 2-hydroxypropanoic acid, 2-phenyl 2-hydroxyethanoic acid, or2,2-diphenyl 2-hydroxyethanoic acid at concentrations of 50% or higherwas prepared according to the examples.

The composition was topically applied to the skin and gently massaged inwith the fingers or a cotton ball by a dermatologist or a trained healthprofessional who wore rubber gloves. After 1 to a few minutes, dependingon the strength used and the skin sensitivity of the subject, the skinwas gently rinsed with water.

Such office treatment was repeated every 2 to 3 weeks. Photographs ofthe skin so treated were taken at the beginning of the study andrepeated at one to three-month intervals as described in the previoussection.

After one to two office treatments, all 32 patients in this particularstudy showed distinct improvement of the face and other areas treated,such as the forearms, the back and the back of hands. The originalcoarse, rough, and dry skin had improved markedly, and the skin wassmooth, glossy, and soft. The number of blotches, blemishes, brownishspots, and age spots decreased significantly after 3 to 5 officetreatments. Facial skin lines and fine wrinkles improved or disappearedin 25 out of this group of 32 patients after 8 to 12 office treatments.

(c) Office Treatment Plus Home Treatment

If rapid therapeutic results are desired, home treatment may be combinedwith the office treatment. After each office treatment, the patientwould topically apply twice daily a composition containing a low tointermediate concentration of a 2-hydroxycarboxylic acid or relatedcompound on the face and the back of hands.

After one office treatment plus twice daily home treatment, all 28patients of this study showed marked improvement on the texture oftreated skin. The rough, coarse, and dry skin disappeared, and the skinwas smooth, glossy, and soft after one month. Blotches, blemishes,nodules, age spots, pigmented spots, skin lines, and fine wrinklesimproved or disappeared, 3 to 5 months after the office treatment plusthe home treatment. Deep wrinkles started to improve visibly as measuredby photographic means after 5 to 10 months of sustained officetreatments and continued home treatments.

Most patients showed marked improvement of deep wrinkles after 12 to 18months of combined office and home treatments.

(d) Epidermolysis and Dermolysis

While the office procedure described in the previous section causes amicro or semimicro peeling of the skin, procedures which causeepidermolysis and dermolysis result in superficial and deeper peeling ofthe skin. When a composition containing a high concentration or a fullstrength of a 2-hydroxycarboxylic acid or related compound such as 70%2-hydroxyethanoic acid, 85% 2-hydroxypropanoic acid, and 100%2-ketopropanoic acid is topically applied to a photodamaged skin,epidermolysis will occur if the time of contact with the skin is longenough. The epidermolysis is clinically beneficial for topical treatmentof acne, age spots, keratoses, pigmented spots, skin lines, blemishes,wrinkles and other signs of skin changes associated with intrinsic andextrinsic aging.

In general, epidermolysis of skin occurs faster on the face than on theupper back or the back of hands, and faster on skin younger people thanof older people. and usually faster in women than men. The clinical signof epidermolysis is blanching of the skin, a sign that signals thethreshold between superficial peeling and deeper peeling. When blanchingof the skin is first seen the skin is immediately rinsed with water toprevent a deeper peeling of the skin.

In dermatologic practice dermolysis or deep peeling has been induced forthe treatment of blemished skin or aging skin by using peeling agentssuch as trichloroacetic acid and phenol. These peeling agents are verycaustic to the skin and are also toxic. Serious side effects includingdeath have been reported. A 2-hydroxycarboxylic acid or related compoundcan be safely used as a micro, semimicro, superficial or deep peelingagent for topical treatment of dermatologic disorders including skinchanges associated with intrinsic aging or skin damages caused byextrinsic aging such as photoaging.

The face of a patient to be so treated was initially wiped with 70%ethanol, and the eyes were covered with wet cotton balls. A fullstrength (100%) 2-ketopropanoic acid, or an aqueous solution containing70% 2-hydroxyethanoic acid or 85% 2-hydroxypropanoic acid was uniformlyapplied to the skin using a cotton ball. The patient usually feel atransient burning sensation. Erythema usually appeared after less than aminute up to a few minutes depending on the skin type, age, sex etc. Theskin was rinsed with water after blanching of the skin occurred orintense erythema persisted.

A total of 23 patients participated in the epidermolysis study. Mostparticipants also daily used emollient lotions or creams containing weakconcentrations of a 2-hydroxycarboxylic acid or related compound. Allthe participants showed marked improvement of skin lines, blemishes andfine wrinkles after 2 months.

(3) Amplified Bioactivities

We have discovered that when a 2-hydroxycarboxylic acid or relatedcompound is incorporated into a composition containing a dermatologicagent, the pharmacologic actions and the therapeutic effects areunexpectedly amplified in most cases. For example, a 2-hydroxycarboxylicacid or related compound magnifies the therapeutic effects ofhydroquinone, 5-fluorouracil, chlorhexidine, clotrimazole, miconazole,tetracycline, retinoic acid etc. Compositions containing2-hydroxycarboxylic acid or the related compound and a dermatological orother pharmaceutical agent were formulated according to the examples.

Each participating patient received two compositions; i.e. with orwithout the incorporation of a 2-hydroxycarboxylic acid or relatedcompound. The patients were instructed to apply topically one medicationon one side of the body such as on the back of the left hand and theother medication on the other side of the body such as on the back ofthe right hand. Specific instructions were given to the patients toapply the medications twice daily to the involved areas or lesions ofblemishes, age spots, melasmas, lentigines, skin lines, wrinkles, orprecancerous actinic keratoses. Clinical improvements were discernibleafter a few weeks to a few months of topical application. The sidestreated with amplified compositions were substantially better than thesides treated with the medications which did not contain any2-hydroxycarboxylic acid or the related compound.

(4) Hair and Nail Treatments

Compositions containing a 2-hydroxycarboxylic acid or related compoundat low concentrations, preferably from 1 to 4%, for hair care andtreatment were formulated according to the examples. A solution or thingel form thus formulated was topically applied to the hair aftershampoo. The same treatment was repeated 3 to 4 times weekly. After afew weeks to a few months of such treatment, the signs of hair changesassociated with intrinsic aging and the damages caused by photoagingstarted to improve substantially. The hair first appeared smooth andshiny. The hair became softer to the touch and feel. After a few monthsof such treatment, hair increased its elasticity and flexibility.

Compositions containing 2-hydroxycarboxylic acid or the related compoundat intermediate concentrations, preferably from 8 to 20%, for nail careand treatment were formulated according to the examples. A solution orthin gel form thus prepared was topically applied twice daily to edges,surface and base of affected nail plates. After a few months of suchtreatment, the signs of nail changes associated with intrinsic andextrinsic aging started to improve noticeably. The nail looked glossyand felt smooth on the surface. The flexibility and elasticity of thenail after the treatment also increased. Brittleness diminished and theoccurrence of terminal nail splitting became rare.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the compositions of matterand methods of this invention. Thus, it is intended that the presentinvention covers such modifications and variations.

What is claimed is:
 1. A method for preventing and/or reducing theappearance of skin changes associated with intrinsic and/or extrinsicaging, said skin changes associated with aging resulting from natural orinnate aging or exposure to actinic radiation,wherein said skin changesassociated with aging are selected from the group consisting ofwrinkles, thinning of the skin, deepening of skin lines, yellowish skin,loss of elasticity, loss of recoilability, and loss of collagen, saidmethod comprising topically applying to the skin a compositioncomprising (i) at least one compound selected from the group consistingof 2-hydroxycarboxylic acids, 2ketoacids and related compounds, ortopically effective salts thereof in an amount and for a period of timesufficient to prevent and/or reduce the appearance of said skin change,and (ii) a sunscreen agent, wherein said 2-hydroxycarboxylic acid isrepresented by a generic structure of:

    (R.sub.a)(R.sub.b)C(OH)COOH

wherein R_(a) and R_(b) may be the same or different and areindependently selected from H, F, Cl, Br, alkyl, aralkyl or aryl groupof saturated or unsaturated, isomeric or non-isomeric, straight orbranched chain or cyclic form, having 1 to 29 carbon atoms, and inaddition R_(a) and R_(b) can be substituted by OH, CHO, COOH and alkoxygroup having 1 to 9 carbon atoms, said 2-hydroxycarboxylic acid may bepresent as a free acid or lactone form, or in a salt form with anorganic base or an inorganic alkali, and as stereoisomers as D, L, andDL forms when R_(a) and R_(b) are not identical, said 2-ketoacid isrepresented by a generic structure of:

    (R.sub.c)COCOO(R.sub.d)

wherein R_(c) and R_(d) may be the same or different and areindependently selected from H, alkyl, aralkyl or aryl group of saturatedor unsaturated, isomeric or non-isomeric, straight or branched chain orcyclic form, having 1 to 29 carbon atoms, and in addition R_(c) maycarry F, Cl, Br, I, OH, CHO, COOH and alkoxy group having 1 to 9 carbonatoms, said alpha ketoacid existing as a free acid or an ester form, orin a salt form with an organic base or an inorganic alkali, and saidrelated compound is selected from the group consisting of quinic acid,isocitric acid, tropic acid, trethocanic acid, 3-chlorolactic acid,cerebronic acid, citramalic acid, agaricic acid, aleuritic acid, pantoicacid, lactobionic acid and hexulosonic acid.
 2. The method of claim 1wherein said 2-hydroxycarboxylic acid is an alkyl hydroxycarboxylic acidwhich is selected from the group consisting of 2-Hydroxyethanoic acid(Glycolic acid), 2-Hydroxypropanoic acid (Lactic acid), 2-Methyl2-hydroxypropanoic acid (Methyllactic acid), 2-Hydroxybutanoic acid,2-Hydroxypentanoic acid, 2-Hydroxyhexanoic acid, 2-Hydroxyheptanoicacid, 2-Hydroxyoctanoic acid, 2-Hydroxynonanoic acid, 2-Hydroxydecanoicacid, 2-Hydroxyundecanoic acid, 2-Hydroxydodecanoic acid (Alphahydroxylauric acid), 2-Hydroxytetradecanoic acid (Alpha hydroxymyristicacid), 2-Hydroxyhexadecanoic acid (Alpha hydroxypalmitic acid),2-Hydroxyoctadecanoic acid (Alpha hydroxystearic acid),2-Hydroxyeicosanoic acid (Alpha hydroxyarachidonic acid),2-Hydroxytetraeicosanoic acid (Cerebronic acid), and2-Hydroxytetraeicosenoic acid (Alpha hydroxynervonic acid).
 3. Themethod of claim 1 wherein said 2-hydroxycarboxylic acid is an aralkyl oraryl 2-hydroxycarboxylic acid which is selected from the groupconsisting of 2-Phenyl 2-hydroxyethanoic acid (Mandelic acid),2,2-Diphenyl 2-hydroxyethanoic acid (Benzilic acid), 3-Phenyl2-hydroxypropanoic acid (Phenyllactic acid), 2-Phenyl 2-methyl2-hydroxyethanoic acid (Atrolactic acid), 2-(4'-Hydroxyphenyl)2-hydroxyethanoic acid, 2-(4'-Chlorophenyl) 2-hydroxyethanoic acid,2-(3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid, 2-(4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid, 3-(2'-Hydroxyphenyl)2-hydroxypropanoic acid, 3-(4'-Hydroxyphenyl) 2-hydroxypropanoic acid,and 2-(3',4'-Dihydroxyphenyl) 2-hydroxyethanoic acid.
 4. The method ofclaim 1 wherein said 2-hydroxycarboxylic acid is a polyhydroxycarboxylicacid or hydroxypolycarboxylic acid which is selected from the groupconsisting of 2,3-Dihydroxypropanoic acid (Glyceric acid),2,3,4-Trihydroxybutanoic acid (Isomers; erythronic acid, threonic acid),2,3,4,5-Tetrahydroxypentanoic acid (Isomers; ribonic acid, arabinoicacid, xylonic acid, lyxonic acid), 2,3,4,5,6-Pentahydroxyhexanoic acid(Isomers; allonic acid., altronic acid, gluconic acid, mannoic acid,gulonic acid, idonic acid, galactonic acid, talonic acid),2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers; glucoheptonic acid,galactoheptonic acid etc.), 2-Hydroxypropane-1,3-dioic acid (Tartronicacid), 2-Hydroxybutane-1,4-dioic acid (Malic acid),2,3-Dihydroxybutane-1,4-dioic acid (Tartaric acid),2-Hydroxy-2-carboxypentane-1,5-dioic acid (Citric acid),2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers; saccharic acid,mucic acid, etc.), and the lactones represented by gluconolactone,galactonolactone, glucuronolactone, galacturonolactone, gulonolactone,ribonolactone, saccharic acid lactone, pantoyllactone,glucoheptonolactone, mannonolactone, and galactoheptonolactone.
 5. Themethod of claim 1 wherein said 2-ketoacid is selected from the groupconsisting of 2-Ketoethanoic acid (Glyoxylic acid), Methyl2-ketoethanoate, 2-Ketopropanoic acid (Pyruvic acid), Methyl2-ketopropanoate (Methyl pyruvate), Ethyl 2-ketopropanoate (Ethylpyruvate), Propyl 2-ketopropanoate (Propyl pyruvate),2-Phenyl-2-ketoethanoic acid (Benzoylformic acid), Methyl2-phenyl-2-ketoethanoate (Methyl benzoylformate), Ethyl2-phenyl-2-ketoethanoate (Ethyl benzoylformate),3-Phenyl-2-ketopropanoic acid (Phenylpyruvic acid), Methyl3-phenyl-2-keotpropanoate (Methyl phenylpyruvate), Ethyl3-phenyl-2-ketopropanoate (Ethyl phenylpyruvate), 2-Ketobutanoic acid,2-Ketopentanoic acid, 2-Ketohexanoic acid, 2-Ketoheptanoic acid,2-Ketooctanoic acid, 2-Ketododecanoic acid, and Methyl 2-ketooctanoate.6. The method of claim 1, wherein said 2-hydroxycarboxylic acid, 2-ketoacid, related compound, topically effective salt, ester or lactonethereof is more than one member selected from the group consisting of2-hydroxyacetic acid; 2-hydroxypropanoic acid; 2-methyl2-hydroxypropanoic acid; 2-hydroxybutanoic acid; phenyl 2-hydroxyaceticacid; phenyl 2-methyl 2-hydroxyacetic acid; 3 -phenyl 2-hydroxypropanoicacid; 2,3-dihydroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;2,3,4,5 -tetrahydroxypentanoic acid; 2,3,4,5,6-pentahydroxyhexanoicacid; 2-hydroxydodecanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoic acid;diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid; 4chloromandelicacid; 3 -hydroxybutanoic acid; 4-hydroxybutanoic acid; 2-hydroxyhexanoicacid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoic acid;10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid; 2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid; 3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3 -methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxyphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid; 2-hydroxypropanedioic acid;2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraricacid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid;galactaric acid; mannaric acid; gularic acid; allaric acid; altraricacid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid;citric acid; isocitric acid; agaricic acid; quinic acid; glucuronicacid; glucuronolactone; galacturonic acid; galacturonolactone; uronicacids; uronolactones; ascorbic acid; dihydroascorbic acid;dihydroxytartaric acid; tropic acid; ribonolactone; gluconolactone;galactonolactone; gulonolactone; mannonolactone; ribonic acid; gluconicacid; citramalic acid; pyruvic acid; hydroxypyruvic acid; hydroxypyruvicacid phosphate; methyl pyruvate; ethyl pyruvate; propyl pyruvate;isopropyl pyruvate; phenyl pyruvic acid; methyl phenyl pyruvate; ethylphenyl pyruvate; propyl phenyl pyruvate; formyl formic acid; methylformyl formate; ethyl formyl formate; propyl formyl formate; benzoylformic acid; methyl benzoyl formate; ethyl benzoyl formate; propylbenzoyl formate; 4hydroxybenzoyl formic acid; 4-hydroxyphenyl pyruvicacid; and 2-hydroxyphenyl pyruvic acid.
 7. The method of claim 1,wherein said extrinsic aging is caused by extrinsic factors selectedfrom the group consisting of sunlight; radiation; air pollution; wind;cold; dampness; heat; chemicals; smoke; and cigarette smoking.
 8. Themethod of claim 1, wherein said sunscreen agent is selected from thegroup consisting of PABA, esters of PABA, dioxybenzone and sulfonamides.9. The method of claim 1, wherein said 2-hydroxycarboxylic acid isglycolic acid.
 10. The method of claim 1, wherein said2-hydroxycarboxylic acid is lactic acid.
 11. The method of claim 1,wherein said 2-hydroxycarboxylic acid is citric acid.
 12. The method ofclaim 1, wherein said 2-hydroxycarboxylic acid, 2-ketoacid or saidrelated compound is in the form of a salt.
 13. The method according toclaim 1, wherein said composition is formulated as a solution, gel,lotion, cream, or ointment.
 14. The method of claim 1, wherein said2-hydroxycarboxylic acid, 2-ketoacid or said related compound is in theform of a free acid.
 15. The method according to claim 1, wherein theperiod of time is at least three months.
 16. The method according toclaim 1, wherein the period of time is at least four months.
 17. Themethod according to claim 1, wherein said topical application is on adaily basis.
 18. The method according to claim 1, wherein said skinchanges associated with aging results from a change in the skin fromnatural or innate aging.
 19. The method according to claim 1, whereinsaid skin changes associated with aging results from a change in theskin from exposure to actinic radiation.
 20. The method according toclaim 1, wherein said compound is the principal ingredient responsiblefor effecting said skin change.
 21. The method according to claim 1,wherein said method results in skin having a more youthful appearance.22. The method of claim 1, wherein said sunscreen agent is PABA or itsesters.
 23. The method of claim 1, wherein said sunscreen agent ispresent in an amount of from 0.01 to 40 percent by weight, based on thetotal weight of the composition.